The present invention relates to 3-amino-1-indanol which is a novel compound and a process for synthesizing it, further to an enantiomerically active compound of 3-amino-1-indanol and a process for enantiomerically resolving it, and to a separating agent for enantiomeric isomers comprising the enantiomerically active compound as an effective ingredient.
Aminoindanols are important intermediates for various fine chemical derivatives including physiologically active substances such as medicines and pesticides. For example, it is disclosed in J. Med. Chem., 35, 2525 (1992), J. Med. Chem., 35, 1702 (1992), J. Med. Chem., 35, 1685 (1992) etc. that cis-1-amino-2-indanol is an effective intermediate for production of anti-HMV drugs.
Moreover, enantiomerically active aminoindanols are effective as separating agents for enantiomerically active carboxylic acids (chiral acids), and JP-A 11-511742 discloses a process for separating chiral acids with 1-aminoindan-2-ol.
3-Amino-1-indanol is a compound also expected to be a synthetic intermediate for medicines and pesticides or a separating agent for chromatography or an enantiomeric resolving agent for racemic bodies, but no body has succeeded in the synthesis thereof and thus it is highly desired to establish the synthetic process.
As a result of the extensive studies for solving the above problems, the present inventors have found out 3-amino-1-indanol which is a novel compound and a convenient process for synthesizing 3-amino-1-indanol using an easily available starting material, further a process for an effective enantiomeric resolution of 3-amino-1-indanol obtained, and a separating agent for enantiomeric isomers comprising an enantiomerically active compound of 3-amino-1-indanol as an effective ingredient. Thus, they have accomplished the present invention.
That is, the present invention provides 3-amino-1-indanol represented by the formula (I): 
wherein the configuration between OH group and NH2 group are cis-configuration or trans-configuration and the compound may be a racemic body or an enantiomerically active compound.
Moreover, the present invention provides a process for synthesizing the 3-amino-1-indanol represented by the above formula (I), which comprises the steps of protecting the amino group of xcex2-phenyl-xcex2-alanine represented by the formula (II): 
with a protective group to give a compound represented by the formula (III): 
(wherein A represents RCO- or ROCO- group (wherein R is an alkyl group having 1 to 30 carbon atoms or an aryl group)); subjecting the compound to Friedel-Crafts acylation to give a compound represented by the formula (IV): 
(wherein A has the same meaning as above); and then removing the protective group of the compound, followed by reduction. Further, it provides an enantiomerically active compound of 3-amino-1-indanol, and a process for enantiomerically resolving 3-amino-1-indanol, which comprises the steps of treating a mixture of enantiomerically active compounds of 3-amino-1-indanol represented by the above formula (I) with an enantiomerically active carboxylic acid; and then separating formed diastereomer salts from each other, and a separating agent for enantiomeric isomers comprising 3-amino-1-indanol represented by the above formula (I) as the effective ingredient. Furthermore, the present invention provides use of the enantiomerically active compound of the 3-amino-1-indanol represented by the above formula (I) as a separating agent for enantiomeric isomers. In addition, the present invention provides a process for enantiomerically separating a racemic body of the target compound to be separated with 3-amino-1-indanol represented by the above formula (I).
3-Amino-1-indanol of the present invention represented by the formula (I) may be cis-isomer or trans-isomer, or a racemic body or an enantiomerically active compound.
xcex2-Phenyl-xcex2-alanine (II) used as a starting material can be synthesized from benzaldehyde, malonic acid, and ammonium acetate according to a known method. The amino group of the resulting xcex2-Phenyl-xcex2-alanine (II) is protected with a protective group using a compound having a group usable as an amino-protecting group, such as acetic anhydride, benzoyl chloride, 9-fluorenylmethyl chloroformate, benzyloxycarbonyl chloride, or di-t-butyl dicarbonate, to give the compound (III). As the amino-protecting group, preferred is acetyl group or benzoyl group, and more preferred is acetyl group. Then, by subjecting the compound (III) to Friedel-Crafts acylation, an indan skeleton-having compound represented by the formula (IV) can be obtained. Friedel-Crafts acylation is effected by first adding PCl5 to the compound (III), reacting them in a solvent such as ethyl ether or THF, and further reacting the product in a solvent such as methylene chloride at a temperature of 0 to 5xc2x0 C. with adding AlCl3. A summary of the above reactions is illustrated in the following reaction scheme. 
wherein A has the same meaning as above; Ac represents acetyl group and Ph represents phenyl group.
Then, by removing the protective group from the resulting compound (IV) and reduction, 3-amino-1-indanol can be obtained. Depending-on the methods for removal of the protective group from the resulting compound (IV) and reduction, the ratio of the trans-isomer and the cis-isomer can be changed, and thereby the trans-isomer or the cis-isomer can be selectively synthesized. The following will describe the process for synthesizing the trans-isomer and the cis-isomer in detail.
First, the following illustrates a summary of the process for synthesizing (xc2x1)-trans-3-amino-1-indanol (racemic body) (I-1) from the compound (IV). 
wherein A has the same meaning as above.
Namely, the trans-isomer of 3-amino-1-indanol represented by the formula (I) can be predominantly obtained in a ratio of trans:cis=3:1 by heating the compound (IV) obtained in the above under reflux under an acidic condition, to give a hydrochloride salt (V) through removal of the protective group, and further reducing the carbonyl group. The reduction of the carbonyl group to hydroxyl group is conducted by means of a metal hydride reagent such as sodium borohydride.
By purifying the mixture (I) of the trans- and cis-isomers, (xc2x1)-trans-3-amino-1-indanol (racemic body) (I-1) can be obtained. As the purifying method, used is preferably made of a method of forming a salt of the mixture (I) with a 2-arylcarboxylic acid such as 2-naphthylacetic acid, heating the salt under reflux, and then allowing to stand at room temperature. By this method, only the salt of the trans-isomer can be selectively crystallized. Subsequently, the above trans-isomer (I-1) can be obtained by treating the salt with an aqueous solution of an alkali selected from sodium hydrogencarbonate, potassium hydrogencarbonate, sodium carbonate, potassium carbonate, sodium hydroxide potassium hydroxide etc, and then extracting with a suitable organic solvent.
Next, the following illustrates a summary of the process for synthesizing (xc2x1)-cis-3-amino-1-indanol (racemic body) (I-2) from the compound (IV). 
wherein A has the same meaning as above; Ac represents acetyl group; and Et represents ethyl group.
Namely, by dissolving the compound (IV) in a suitable solvent and subjecting it to reduction with, for example, sodium borohydride, cis-isomer of (xc2x1)-N-acyl-3-aminoindan-1-ol (VI) can be predominantly obtained in a ratio of cis:trans=3:1. At that time, the reaction solvent is preferably tetrahydrofuran (THF). Moreover, the reaction temperature is preferably from xe2x88x92100 to xe2x88x9250xc2x0 C. Then, the resulting mixture (VI) of the cis- and trans-isomers are purified by a chromatography, recrystallization or the like, to give (xc2x1)-cis-N-acyl-3-aminoindan-1-ol (VII).
(xc2x1)-cis-3-Amino-1-indanol (racemic body) (I-2) can be obtained by heating the resulting (xc2x1)-cis-N-acyl-3-aminoindan-1-ol (VII) in a suitable basic organic solvent under reflux and then extracting with a suitable solvent. At-that time, the basic organic solvent is preferably a sodium hydroxide-ethanol mixed solvent and the extracting solvent is preferably methylene chloride.
The enantiomeric resolution of the racemic body of 3-amino-1-indanol can be conducted according to a diastereomer salt method using an enantiomerically active carboxylic acid. The usable enantiomerically active carboxylic acid is not particularly limited but it is preferable to use dibenzoyltartaric acid because an enantiomerically active compound can be efficiently obtained.
The solvent used at the enantiomeric resolution is not particularly limited but preferred is a water-ethanol mixed solvent. The crystallizing temperature may be in the range of 0 to 60xc2x0 C., preferably the range of 10 to 40xc2x0 C. If necessary, the crystallized diastereomer salt may be recrystallized to give a crystalline diastereomer salt having a higher enantiomeric purity.
The enantiomerically active compound of 3-amino-1-indanol obtained as above is useful as a separating agent for enantiomeric isomers, particularly an enantiomeric resolving agent for the racemic body of an enantiomerically active carboxylic acid.
In the enantiomeric resolution of an enantiomerically active carboxylic acid using 3-amino-1-indanol, an enantiomerically active carboxylic acid can be obtained by the method of mixing an enantiomerically active compound of 3-amino-1-indanol and the racemic body of an enantiomerically active carboxylic acid in a suitable solvent and then precipitating a diastereomer salt. In particular, a carboxylic acid having an aryl group at the 2-position can be preferably enantiomerically resolved.
Novel 3-amino-1-indanol of the present invention is an extremely important compound as an synthetic intermediate for medicines and pesticides, especially for medicines. Furthermore, enantiomerically active 3-amino-1-indanol can be widely utilized also as a separating agent for enantiomerically active carboxylic acids.